Eli Lilly and Company announced positive topline results from the Phase 3 TRIUMPH-4 clinical trial evaluating the safety and efficacy of the two highest investigational doses of retatrutide, a first-in-class GIP, GLP-1 and glucagon triple hormone receptor agonist, in adults with obesity or overweight and knee osteoarthritis, and without diabetes, as an adjunct to healthy diet and physical activity. In this global registration trial, where 84.0% of participants had a baseline BMI of ≥35 kg/m², each dose of retatrutide (9 mg and 12 mg) met all primary and key secondary endpoints, delivering significant weight loss and improvements in pain and physical function at 68 weeks using both the efficacy and treatment-regimen estimands. For the co-primary endpoints, retatrutide lowered weight by up to an average of 28.7% (71.2 lbs) and reduced pain by up to an average of 4.5 points (75.8%) using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score.
"People with obesity and knee osteoarthritis often live with pain and restricted mobility, and may eventually require total joint replacement," said Kenneth Custer, Ph.D., executive vice president and president, Lilly Cardiometabolic Health. "We are encouraged by the results of TRIUMPH-4, which highlight the powerful effect of retatrutide, a first-in-class triple agonist, on body weight, pain and physical function. With seven additional Phase 3 readouts expected in 2026, we believe retatrutide could become an important option for patients with significant weight loss needs and certain complications, including knee osteoarthritis."
In additional secondary endpoints, retatrutide reduced known markers of cardiovascular risk, including non-HDL cholesterol, triglycerides, and high-sensitivity C-reactive protein (hsCRP), and at the highest dose lowered systolic blood pressure by 14.0 mmHg, using the efficacy estimand. In an additional post-hoc analysis, 14.1% of patients on retatrutide 9 mg and 12.0% patients on retatrutide 12 mg were completely free of knee pain at 68 weeks compared to 4.2% on placebo, based on the observed efficacy estimand data.
For the treatment-regimen estimand, each dose level of retatrutide led to statistically significant improvements in both co-primary and all secondary endpoints. The treatment-regimen estimand results for the co-primary endpoints were:
Percent change in body weight: -20.0% (-22.9 kg; -50.5 lbs; 9 mg); -23.7% (-27.2 kg; -60.0 lbs; 12 mg) and -4.6% (-5.3 kg; -11.7 lbs; placebo)
Change in WOMAC pain subscale score: -4.0 points (-67.2%; 9 mg), -3.7 points (-62.6%; 12 mg) and -2.1 points (-35.1%; placebo)
Consistent with the types of adverse events seen in clinical trials for other incretins, the most common adverse events among participants treated with retatrutide (9 mg and 12 mg, respectively) were nausea (38.1% and 43.2%) vs. 10.7% with placebo, diarrhea (34.7% and 33.1%) vs. 13.4% with placebo, constipation (21.8% and 25.0%) vs. 8.7% with placebo, vomiting (20.4% and 20.9%) vs. 0.0% with placebo, and decreased appetite (19.0% and 18.2%) vs. 9.4% with placebo. Dysesthesia occurred in 8.8% and 20.9% (9 mg and 12 mg, respectively) of patients treated with retatrutide, compared to 0.7% with placebo. These dysesthesia events were generally mild and rarely led to treatment discontinuation. Overall treatment discontinuation rates were similar across the retatrutide and placebo treatment arms. Discontinuation rates due to adverse events were 12.2% and 18.2% with retatrutide 9 mg and 12 mg, respectively, compared to 4.0% with placebo. These rates were highly correlated with baseline BMI and included discontinuations for perceived excessive weight loss. For patients with a baseline BMI ≥35, discontinuation rates due to adverse events were 8.8% and 12.1% for the 9 mg and 12 mg doses, respectively, compared to 4.8% with placebo.
Detailed TRIUMPH-4 results will be presented at a future medical meeting and published in a peer-reviewed journal. Additional results from the TRIUMPH program, which include a maintenance dose of 4 mg in addition to the 9 mg and 12 mg doses tested in this trial, are expected in 2026.
About retatrutide
Retatrutide is an investigational once-weekly triple hormone receptor agonist. Retatrutide is a single molecule that activates the body's receptors for glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon. Lilly is studying retatrutide in several Phase 3 clinical trials to evaluate its potential efficacy and safety in obesity and overweight with at least one weight-related medical problem, type 2 diabetes, knee osteoarthritis, moderate-to-severe obstructive sleep apnea, chronic low back pain, cardiovascular and renal outcomes, and metabolic dysfunction-associated steatotic liver disease.
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